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Chang, Y., Sun, L., Kokura, K., Horton, J.R., Fukuda, M., Espejo, A., Izumi, V., Koomen, J.M., Bedford, M.T., Zhang, X., Shinkai, Y., Fang, J. and Cheng, X. (2011) MPP8 mediates the interactions between DNA methyltransferase Dnmt3a and H3K9 methyltransferase GLP/ G9a. Nature Communications, 2, 533. doi:10.1038/ncomms1549

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• TITLE: A conformational B-Z DNA study monitored with phosphatemethylated DNA as a model for epigenetic dynamics focused on 5-(hydroxy)methylcytosine

  AUTHORS: Henk M. Buck

  KEYWORDS: B-Z DNA Transition; Artificial DNA’s; Epigenetics; Phosphorylation-Demethylation; Alzheimer

  JOURNAL NAME: Journal of Biophysical Chemistry, Vol.4 No.2, May 24, 2013

  ABSTRACT: This study was directed on the B- into Z-DNA isomerization with alternating CG sequences monitored with artificial DNA model-systems based on methylation of the phosphate backbone. The chemical concept for this transition wherein shielding of the oxygen anions of the backbone phosphates plays an essential role, resulted in the preparation of the phosphatemethylated d(CpG). Even on this primitive level of only two base pair long, the B-Z conformational aspects of this self-complementary duplex could be described in solution with nuclear magnetic resonance (NMR) and circular dichroism (CD) measurements. The exclusivity of this choice became clear after synthesizing phosphatemethylated DNA with longer alternating CG fragments. It could be shown that conflicting conformational effects of the CG and GC fragments resulted in an overall B structure of the phosphatemethylated tetramer d(CPGPCPG). From our model considerations, it is clear that the internal stress introduced by the alternating CG sequences will be promoted by a complete shielding of the phosphate backbone. Elimination of this effect may be realized by a site-specific phosphate shielding. The role of the anti-syn isomerization of G in the CG fragments is clarified by methylation of the phosphate group. This anti-syn transition is absent in corresponding methylphosphonates, suggesting an exclusive role for base-backbone coordination via hydrogen bonding. In addition, we propose that the B- into Z-DNA interconversion may offer a mechanistic view for differences in dynamics between cytosine and its epigenetic derivative 5-methylcytosine. This mechanism has been extended to the demethylation of 5-methylcytosine and the exchange of information between the new epigenetic base, 5-hydroxymethylcytosine and the DNA backbone via an intramolecular phosphorylation. The role of 5-hydroxymethylcytosine in Alzheimer disease has been briefly discussed. In our opinion, this study can be considered as a new dynamic concept for epigenetics based on the dynamics of the B-Z transition in natural and phosphatemethylated DNA.